Novel 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity

ABSTRACT

The present invention relates to a group of novel 4,5-dihydro-1H-pyrazo, derivatives which are potent cannabinoid (CB1) receptor antagonists with utility for the treatment of diseases connected with disorders of the cannabinoid system. The compounds have the general formula (I) wherein the symbols have the meanings given in the specification. The invention also relates to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.

[0001] The present invention relates to a group of novel 4,5-dihydro-1H-pyrazole derivatives, to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.

[0002] The above mentioned 4,5-dihydro-1H-pyrazoles are potent cannabinoid (CB₁) receptor antagonists with utility for the treatment of diseases connected with disorders of the cannabinoid system.

[0003] Cannabinoids are present in the Indian hemp Cannabis sativa and have been used as medicinal agents for centuries (Mechoulam, R. and Feigenbaum, J. J. Prog. Med. Chem. 1987, 24, 159). However, only within the past ten years the research in the cannabinoid area has revealed pivotal information on cannabinoid receptors and their (endogenous) agonists and antagonists. The discovery and the subsequent cloning of two different subtypes of Cannabinoid receptors (CB₁ and CB₂) stimulated the search for novel cannabinoid receptor antagonists (Munro, S. et al., Nature 1993, 365, 61. Matsuda, L. A. and Bonner, T. I. Cannabinoid Receptors, Pertwee, R. G. Ed. 1995, 117, Academic Press, London). In addition, pharmaceutical companies became interested in the development of cannabinoid drugs for the treatment of diseases connected with disorders of the cannabinoid system (Consroe, P. Neurobiology of Disease 1998, 5, 534. Pop, E. Curr. Opin. In CPNS Investigational Drugs 1999, 1, 587. Greenberg, D. A. Drug News Perspect. 1999, 12, 458. Pertwee, R. G., Progress in Neurobiology 2001, 63, 569). Hitherto, several CB₁ receptor antagonists are known. Sanofi disclosed their diarylpyrazole congeners as selective CB₁ receptor antagonists. A representative example is SR-141716A (Dutta, A. K. et al., Med. Chem. Res. 1994, 5, 54. Lan, R. et al., J. Med. Chem. 1999, 42, 769. Nakamura-Palacios, E. M. et al., CNS Drug Rev. 1999, 5, 43). CP-272871 is a pyrazole derivative, like SR141716A, but less potent and less CB₁ receptor subtype-selective than SR141716A (Meschler, J. P. et al., Pharmacol. 2000, 60, 1315). Aminoalkylindoles have been disclosed as CB₁ receptor antagonists. A representative example is lodopravadoline (AM-630), which was introduced in 1995. AM-630 is a moderately active CB₁ receptor antagonist, but sometimes behaves as a weak partial agonist (Hosohata, K. et al., Life Sc. 1997, 61, PL115). Researchers from Eli Lilly described aryl-aroyl substituted benzofurans as selective CB₁ receptor antagonists (e.g. LY-320135) (Felder, C. C. et al., J. Pharmacol. Exp. Ther. 1998, 284, 291). 3-Alkyl-5,5′-diphenylimidazolidinediones were described as cannabinoid receptor ligands, which were indicated to be cannabinoid antagonists (Kanyonyo, M. et al., Biorg. Med. Chem. Left. 1999, 9, 2233). Aventis Pharma claimed diarylmethyleneazetidine analogs as CB₁ receptor antagonists (Mignani, S. et al., Patent FR 2783246, 2000; Chem. Abstr. 2000, 132, 236982). Tricyclic pyrazoles were claimed by Sanofi-Synthelabo as CB₁ antagonists (Barth, F. et al., Chem. Abstr 2001, 134, 340504). Interestingly, many CB₁ receptor antagonists have been reported to behave as inverse agonists in vitro (Landsman, R. S. et al., Eur. J. Pharmacol. 1997, 334, R1). Reviews provide a nice overview of the cannabinoid research area (Mechoulam, R. et al., Prog. Med. Chem. 1998, 35, 199. Lambert, D. M. Curr. Med. Chem. 1999, 6, 635. Mechoulam, R. et al., Eur. J. Pharmacol. 1998, 359, 1. Williamson, E. M. and Evans, F. J. Drugs 2000, 60, 1303. Pertwee, R. G. Addiction Biology 2000, 5, 37. Robson, P. Br. J. Psychiatry 2001, 178, 107. Pertwee, R. G. Prog. Neurobiol. 2001, 63, 569. Goya, P; Jagerovic, N. Exp. Opin. Ther. Patents 2000, 10, 1529. Pertwee, R. G. Gut 2001, 48, 859).

[0004] It has now surprisingly been found that potent and selective antagonism of cannabinoid-CB₁ receptors is present in the novel 4,5-dihydro-1H-pyrazole derivatives of the formula (I), prodrugs thereof, tautomers thereof and salts thereof

[0005] wherein

[0006] R and R₁ independently represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group C₁₋₃-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C₁₋₂)-amino, mono- or dialkyl (C₁₋₂)-amido, (C₁₋₃)-alkyl sulfonyl, dimethylsulfamido, C₁₋₃-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R₁ represent naphtyl,

[0007] R₂ represents hydrogen, hydroxy, C₁₋₃-alkoxy, acetyloxy or propionyloxy,

[0008] R₃ represents a hydrogen atom or a branched or unbranched C₁₋₈ alkyl group or a C₃₋₇ cycloalkyl group which alkyl group or cycloalkyl group may be substituted with a hydroxy group,

[0009] R₄ represents a C₂₋₁₀ branched or unbranched heteroalkyl group, C₃₋₈ non-aromatic heterocycloalkyl group or C₄₋₁₀ non-aromatic heterocycloalkyl-alkyl group which groups contain one or more heteroatoms from the group (O, N, S) or a —SO₂— group, which C₂₋₁₀ branched or unbranched heteroalkyl group, C₃₋₈ non-aromatic heterocycloalkyl group or C₄₋₁₀ non-aromatic heterocycloalkyl-alkyl group may be substituted with a keto group, trifluoromethyl group, C₁₋₃ alkyl group, hydroxy, amino, monoalkylamino, or dialkylamino group or a fluoro atom, or R₄ represents an amino, hydroxy, phenoxy or benzyloxy group, or R₄ represents a C₁₋₈ alkoxy, C₃₋₈ alkenyl, C₅₋₈ cycloalkenyl or C₆₋₉ cycloalkenylalkyl group which groups may contain a sulphur, nitrogen or oxygen atom, a keto group or —SO₂— group, which alkoxy, alkenyl and cycloalkenyl groups may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino group or dialkylamino group or a fluoro atom, or R₄ represents a C₂₋₅ alkyl group which alkyl group contains a fluoro atom, or R₄ represents an imidazolylalkyl group, benzyl, pyridylmethyl, phenethyl or thienyl group, or R₄ represents a substituted phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl group wherein the aromatic rings are substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning as indicated above,

[0010] or when R₃ is H or methyl, R₄ may represent a group NR₆R₇ wherein

[0011] R₆ and R₇ are the same or different and represent C₂₋₄ alkyl , C₂₋₄ trifluoroalkyl or R₆ represents a methyl group with the proviso that R₇ represents a C₂₋₄ alkyl group, or R₆ and R₇—together with the nitrogen atom to which they are bonded—form a saturated or unsaturated heterocyclic moiety having 4 to 8 ring atoms which heterocyclic moiety may contain an oxygen or sulphur atom or a keto group or —SO₂— group or an additional nitrogen atom, which saturated or unsaturated heterocyclic moiety may be substituted with a C₁₋₄ alkyl group, or

[0012] R₃ and R₄ together with the nitrogen atom to which they are bonded form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic moiety may contain one or more atoms from the group (O, N, S) or a keto group or —SO₂— group, which moiety may be substituted with a C₁₋₄ alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl group,

[0013] R₅ represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1, 2, 3 or 4 substituents Y, wherein Y has the meaning as indicated above, which can be the same or different, or R₅ represents C₁₋₈ branched or unbranched alkyl, C₃₋₈ alkenyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ bicycloalkyl, C₆₋₁₀ tricycloalkyl or C₅₋₈ cycloalkenyl or R₅ represents naphtyl.

[0014] At least one centre of chirality is present (at the C₄ position of the 4,5-dihydro-1H-pyrazole moiety) in the compounds of the formula (I). The invention relates both to racemates, mixtures of diastereomers and the individual stereoisomers of the compounds having formula (I). Particular compounds of interest of formula (I) have the absolute stereoconfiguration at the C₄ position of the 4,5-dihydro-1H-pyrazole moiety as represented by formula (1^(a)).

[0015] The invention also relates both to the E isomer, Z isomer and E/Z mixtures of compounds having formula (I).

[0016] The compounds of the invention can be brought into forms suitable for administration by means of usual processes using auxiliary substances and/or liquid or solid carrier materials.

[0017] Due to the potent CB₁ antagonistic activity the compounds according to the invention are suitable for use in the treatment of psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders.

[0018] The affinity of the compounds of the invention for cannabinoid CB₁ receptors was determined using membrane preparations of Chinese hamster ovary (CHO) cells in which the human cannabinoid CB₁ receptor is stably transfected in conjunction with [³H]CP-55,940 as radioligand. After incubation of a freshly prepared cell membrane preparation with the [³H]-ligand, with or without addition of compounds of the invention, separation of bound and free ligand was performed by filtration over glassfiber filters. Radioactivity on the filter was measured by liquid scintillation counting.

[0019] The cannabinoid CB₁ antagonistic activity of compounds of the invention was determined by functional studies using CHO cells in which human cannabinoid CB₁ receptors are stably expressed. Adenylyl cyclase was stimulated using forskolin and measured by quantifying the amount of accumulated cyclic AMP. Concomitant activation of CB₁ receptors by CB₁ receptor agonists (e.g. CP-55,940 or (R)-WIN-55,212-2) can attenuate the forskolin-induced accumulation of cAMP in a concentration-dependent manner. This CB₁ receptor-mediated response can be antagonised by CB₁ receptor antagonists such as the compounds of the invention.

[0020] Intermediates having formula (II) (see below) can be obtained according to methods known, for example: a) Francotte, E. and Tong, Z. Chem. Abstr. 126, 213598; b) Rempfler, H. and Kunz, W. Chem. Abstr. 113, 40432; c) Rempfler, H. and Kunz, W. Chem. Abstr. 107, 217473.

[0021] Intermediates having formula (III) (see below), wherein R₂ represents hydrogen can be obtained according to methods known, for example: a) EP 0021506; b) DE 2529689; c) Grosscurt, A. C. et al., J. Agric. Food Chem. 1979, 27, (2), 406.

[0022] Intermediates having formula (III) (see below), wherein R₂ represents a hydroxy group can be obtained by reacting of a compound having formula (II)

[0023] with hydrazine or hydrazine hydrate. This reaction is preferably carried out in an organic solvent, for example ethanol, and yields a compound having formula (III)

[0024] Suitable synthetic routes for the compounds of the invention are the following:

[0025] Synthetic Route A1

[0026] Step 1: reaction of a compound having formula (III) with a thioisocyanate derivative having formula (IV),

[0027] preferably carried out in an organic solvent, for example acetonitrile. This reaction gives a thiocarboxamide derivative having formula (V), wherein R, R₁, R₂ and R₅ have the meanings as described above for compound (I).

[0028] Step 2: reaction of a compound having formula (V) with a compound R₃R₄NH in the presence of a mercury(II) salt, such as for example HgCl₂, gives a compound having formula (I). This reaction is preferably carried out in an organic solvent, such as for example acetonitrile.

[0029] Synthetic Route A2

[0030] Step 1: reaction of a compound having formula (III)

[0031] with a carbamate ester derivative having formula (VI).

[0032] wherein R₈ represents a lower alkyl group, for example methyl. This reaction is preferably carried out in an organic solvent, for example 1,4-dioxane, and yields a 4,5-dihydropyrazole-1-carboxamide derivative having formula (VII), wherein R, R₁, R₂ and R₅ have the meanings as described above for compound (I).

[0033] Step 2: reaction, preferably carried out in an inert organic solvent, for example chlorobenzene, of a compound having formula (VII) with a halogenating agent such as PCl₅, gives a 4,5-dihydropyrazole-1-carboximidoyl halogenide derivative having formula (VIII) wherein R, R₁, R₂, R₅ have the meanings as described above for compound (I) and wherein R₉ represents a halogen atom, for example Cl.

[0034] Step 3: reaction of a compound having formula (VII) with a compound R₃R₄NH preferably carried out in an inert organic solvent, such as for example dichloromethane gives a compound having formula (I).

[0035] Alternatively, compounds R₃R₄NH which contain an additional nucleophilic nitrogen atom are reacted with a compound having formula (VIII) in such a way that the abovementioned additional nucleophilic nitrogen atom is protected by a protective group, for example a t-butoxycarbonyl (Boc) group and the like. Subsequent removal of the protective group according to known methods yields a compound having formula (I). (See for example: T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, third edition, John Wiley & Sons, Inc., New York, 1999).

[0036] Synthetic Route A3

[0037] Step 1: reaction of a compound having formula (III)

[0038] with a dithioimidocarbonic ester derivative having formula (IX).

[0039] wherein R₁₀ represents a C₁₋₃ alkyl group. This reaction is preferably carried out in an organic solvent, for example acetonitrile or toluene, and yields a carboximidothioic ester derivative having formula (X), wherein R, R₁, R₂, R₅ have the meanings as described above for compound (1) and wherein R₁₀ represents a C₁₋₃ alkyl group.

[0040] Alternatively, a compound having formula (X) can be obtained from the reaction of a compound having formula (V) with a compound R₁₀—X, wherein X represents a leaving group such as an iodide group, and R₁₀ has the meaning as described above for (X).

[0041] Step 2: Reaction, preferably carried out in an organic solvent, such as methanol, of a compound having formula (X) with a compound R₃R₄NH gives a compound having formula (I).

[0042] The preparation of the compounds is illustrated in the following examples.

EXAMPLE 1 3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-(piperidin-1 -yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1 -carboxamidine

[0043] Part A: To a solution of N-((4-chlorophenyl)sulfonyl)carbamic acid methyl ester (CAS: 34543-04-9) (2.99 gram, 12.0 mmol) and pyridine (4 mL) in 1,4-dioxane (20 mL) is added 3-(4-chlorophenyl)-4-phenyl4,5-dihydro-1H-pyrazole (3.39 gram, 13.2 mmol) and the resulting mixture is stirred for 4 hours at 100° C. After concentration in vacuo the residue is dissolved in dichloromethane, successively washed with water, 1 N HCl and water, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to a volume of 20 mL. Methyl-tert-butyl ether (60 mL) is added and the resulting solution is concentrated to a volume of 20 mL. The formed crystals are collected by filtration and recrystallised from methyl-tert-butyl ether to give 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl4,5-dihydro-1H-pyrazole-1-carboxamide (4.75 gram, 76% yield) Melting point: 211-214° C.

[0044] Part B: A mixture of 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)4-phenyl4,5-dihydro-1H-pyrazole-1-carboxamide (1.42 gram, 3.00 mmol) and phosphorus pentachloride (PCl₅) (0.63 gram, 3.03 mmol) in chlorobenzene (15 mL) is heated at reflux temperature for 1 hour. After thorough concentration in vacuo, the formed 3-(4-chlorophenyl)-N-((4-chlorophenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidoyl chloride is suspended in dry dichloromethane (30 mL) and reacted 1-aminopiperidine (1.08 mL, 10.0 mmol). After stirring at room temperature for 16 hours, the mixture is twice washed with water and concentrated in vacuo. The residue is crystallised from methyl-t-butyl ether (MTBE) to give pure 3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-(piperidin-1-yl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (0.57 gram, 34% yield). Melting point (MP): 213-214° C. MS ESI⁺: 556 (MH⁺).

[0045] Analogous to the synthesis of example 1, in total 57 compounds having formula (XI) were prepared. Those are listed below in table 1 and list 1. TABLE 1 (XI)

Melting MS ESI⁺ Salt Ex. R₃ R₄ R₁₁ point (° C.) (MH⁺) form 2 H Piperidin-1-yl F 189-190 540 3 H Pyrrolidin-1-yl Cl 190-195 542 4 H Pyrrolidin-1-yl F 526 5 H azepan-1-yl Cl 197-199 6 H Cis/trans-2,6-dimethylpiperidin-1-yl Cl 110-146 7 H 2,2,2-Trifluoroethylamino Cl 149-151 8 H t-Butoxy Cl 194-196 545 9 H 2-Propoxy Cl 142-145 10 H Methoxy Cl 503 11 H Methoxy F 487 12 H Morpholin-4-yl Cl 213-216 13 H 2-(Morpholin-4-yl)ethyl Cl 137-139 14 H 2-(Piperidin-1-yl)ethyl Cl 168-169 15 H 2-(Pyrrolidin-1-yl)ethyl Cl 155-157 16 H 2-(Dimethylamino)ethyl F 17 CH₃ 2-(Dimethylamino)ethyl Cl 168-170 .HCl 18 H 2-(Dimethylamino)ethyl Cl 63-68 19 H 2-(Methylamino)ethyl Cl 530 .HCl 20 H 2-(Ethylamino)ethyl Cl 544 .HCl 21 H 3-(Dimethylamino)-2-methylprop-2-yl Cl 572 22 H (N-Methylpyrrolidin-2-yl)methyl Cl 149-159 23 H (N-Methylpyrrolidin-3-yl)methyl Cl 570 24 H 4-(Pyrrolidin-1-yl)butyl Cl 128-130 598 25 H 3-(Morpholin-4-yl)propyl Cl 26 H 3-(Dimethylamino)propyl Cl 221-224 558 .HCl 27 CH₃ 3-(Dimethylamino)propyl F 93 (dec.) 556 .HCl 28 C₂H₅ 2-Aminoethyl Cl 29 H 3-(Dimethylamino)propyl F 105-109 542 .HCl 30 H 3-(1H-Imidazol-1-yl)propyl Cl 31 H 2-Aminoxyethyl Cl 532 32 H 2-(Dimethylamino)ethoxy Cl 201 560 33 H 2-(Diethylamino)ethoxy Cl 210 588 34 H 2-(Methoxy)ethyl Cl  99-102 35 CH₃ 2-(Acetoxy)ethyl Cl 157-158 573 36 H 2-Hydroxyethyl F 501 37 H 2-Hydroxyethyl Cl 517 38 H 2-Hydroxy-2-methylpropyl Cl 39 H 3-Hydroxypropyl Cl 129-132 40 CH₃ Hydroxy Cl 208-211 41 H Methoxy CF₃ 178-180 42 H 2-Fluoroethyl Cl 100-103 43 H 2-Fluoroethyl CF₃ 132-134

[0046] List 1

[0047] 44. 3-(4-Chlorophenyl)-N-methoxy-N′-((3-methylphenyl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 151-152° C.

[0048] 45. 3-(4-Chlorophenyl)-N-methoxy-N′-((2-methylphenyl)sulfonyl)4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 145-146° C.

[0049] 46. 3-(4-Chlorophenyl)-N-methoxy-N′-((2,4,5-trifluorophenyl)sulfonyl)4-phenyl4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 160-162° C.

[0050] 47. 3-(5-Chlorothien-2-yl)-N′-((4-chlorophenyl)sulfonyl)-N-methoxy-4-phenyl4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 180-181° C.

[0051] 48. N′-((4-Chlorophenyl)sulfonyl)-3-(4-fluorophenyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 201-203° C.

[0052] 49. 3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-methoxy4-(3-(trifluoromethyl)phenyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine.MP: 80-83° C.

[0053] 50. 3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-methoxy4-(2,6-difluorophenyl)4,5-dihydro-1H-pyrazole-1-carboxamidine.MP: 174-177° C.

[0054] 51. 3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-(2-fluoroethyl)4-(2,6-difluorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 153-155° C.

[0055] 52. 3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-(2-fluoroethyl)4-(3-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 130° C.

[0056] 53. 3-(4-Chlorophenyl)-N-(2-fluoroethyl)4-(3-fluorophenyl)-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 155° C.

[0057] 54. 3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)4-(3-fluorophenyl)-N-(methoxy)4,5-dihydro-1H-pyrazole-1-carboxamidine. Amorphous.

[0058] 55. 3-(4-Chlorophenyl)-4-(3-fluorophenyl)-N-(methoxy)-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: >260° C.

[0059] 56. 3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-4-(2-fluorophenyl)-N-(methoxy)-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 162-164° C.

[0060] 57. 3-(4-Chlorophenyl)-4-(2-fluorophenyl)-N-(methoxy)-N′-((4-(trifluoromethyl)phenyl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine. MP: 147-149° C.

[0061] In an analogous manner 29 compounds having formula (XII) were prepared. Those are listed below in table 2 and list 2. TABLE 2 (XII)

Melting MS ESI⁺ Salt Ex. R₁₁ R₁₂ point (° C.) (MH⁺) form 58 Cl 1,2,3,4-Tetrahydroisoquinolin-2-yl 589 59 F 1,2,3,4-Tetrahydroisoquinolin-2-yl 573 60 F Pyrrolidin-1-yl 511 61 F Morpholin-4-yL 543 62 F Morpholin-4-yl 527 63 Cl Azetidin-1-yl 200-202 513 64 F Azetidin-1-yL 497 65 Cl 4-Hydroxypiperidin-1-yl 112-117 66 Cl 3-Hydroxypiperidin-1-yl 218-222 67 Cl 4-(Hydroxymethyl)piperidin-1-yl 185-188 68 Cl 1,1-Dioxythiomorpholin-4-yl 120 591 69 Cl 4-Methylpiperazin-1-yl 556 70 Cl [1,4′]-Bipiperidin-1′-yl 260 624 71 Cl 3,5-Cis-dimethylpiperazin-1-yl 72 F 4-Methylpiperazin-1-yl 540 73 F 3,5-Cis-dimethylpiperazin-1-yl 554 74 F [1,4′ -Bipiperidin-1′-yl >280 608 75 F 4-Methyl-1,4-diazepan-1-yl 115 554 .HCl 76 Cl 1,4-diazepan-1-yl 84 77 F 1,4-diazepan-1-yl 78 Cl 2,6-Cis-dimethylpiperazin-1-yl   100 (dec.) 79 F 4-(Dimethylamino)piperidin-1 -yl 211-214 80 F Piperazin-1-yl 88-90 81 Cl 4-(Pyridin-4-yl)piperazin-1-yl 224-226 82 Cl 4-(2-Dimethylaminoethyl)piperazin-1-yl 83 Cl 4-(3-Dimethylaminopropyl)piperazin-1-yl 163-165 84 Cl 4-(3-Hydroxypropyl)piperazin-1-yl >140 (dec.) 85 Cl 2,6-Cis-dimethyl-4-methylpiperazin-1-yl 75-80

[0062] List 2

[0063] 86. N-[(3-(4-chlorophenyl)-4-(3-(trifluoromethyl)phenyl)4,5-dihydro-1H-pyrazol-1-yl)(4-methylpiperazin-1-yl)methylene]-4-chlorobenzenesulfonamide. MP: 97-100° C.

[0064] In an analogous manner the compounds having formula (XIII) have been prepared. Those are listed in table 3 or detailed below: TABLE 3 (XIII)

Melting Exam- point MS ESI⁺ ple R₃ R₄ R₁₃ (° C.) (MH⁺) 87 H 3-(Dimethylamino)propyl CH₃ 136-138 88 H N-Methylpiperidin-4-yl i-C₃H₇

EXAMPLE 89 N-[(4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(4-methylpiperazin-1-yl)methylene]-4-fluorobenzenesulfonamide

[0065] Part A: 3-Pyridyl benzyl ketone (Cf. Burger et al., J. Am. Chem. Soc. 1950, 72, 1988-1990), (30.2 g, 0.153 mol) is dissolved in methanol (400 mL) and acetic acid (1.5 mL), piperidine (1.5 mL) and formaline (35 mL, 37% aqueous solution) are sucessively added. The resulting mixture is heated at reflux temperature for 210 minutes. The resulting mixture is allowed to attain room temperature and concentrated in vacuo. Water and 2N NaOH solution are added, followed by extraction with methyl-t-butyl ether (MTBE). The organic layer is twice washed with water, dried over Na₂SO₄, filtered and concentrated in vacuo. Flash chromatographic purification (eluant: MTBE) gives 2-phenyl-1-pyridin-3-yl propenone (21.4 gram, 67% yield) as an oil. ESI-MS (MH⁺) 210.

[0066] Part B: 2-Phenyl-1-pyridin-3-yl propenone (21.4 gram, 0.102 mol) is dissolved in ethanol (150 mL) and hydrazine hydrate is added (10.4 mL). The resulting mixture is heated at reflux temperature for 3 hours. The resulting mixture is allowed to attain room temperature and concentrated in vacuo. Water is added, followed by extraction with dichloromethane. The organic layer is washed with water, dried over Na₂SO₄, filtered and concentrated in vacuo to produce crude 4-phenyl-3-(pyridin-3-yl)4,5-dihydro-1H-pyrazole (23 g, ˜100% yield). ESI-MS (MH⁺) 224.

[0067] Part C: Crude 4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole (9.81 g, 0.044 mol), [(4-chlorophenyl)sulfonyl]dithioimidocarbonic acid dimethyl ester (12.99 gram, 0.044 mol) and triethylamine (47 mL) are successively dissolved in acetonitrile. The resulting mixture is heated at reflux for 70 hours. The resulting mixture is allowed to attain room temperature and concentrated in vacuo. The residue is dissolved in dichloromethane. The organic layer is washed with water, dried over Na₂SO₄, filtered and concentrated in vacuo. Flash chromatographic purification (eluant: methanol/dichloromethane=5/95 (v/v)) gives N-((4-chlorophenyl)sulfonyl)-4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (7.15 gram, 35% yield). ESI-MS (MH⁺) 471.

[0068] Part D: N-((4-Chlorophenyl)sulfonyl)4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (1.50 gram, 0.0033 mol) is suspended in toluene (25 mL) and 4-methylpiperazine (5 mL) is added. The resulting mixture is heated at 60° C. for 70 hours. The resulting yellow solution is allowed to attain room temperature and concentrated in vacuo. The resulting residue is crystallised from MTBE to give N-[(4-phenyl-3-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-1-yl)(4-methylpiperazin-1-yl)methylene]4-fluorobenzene-sulfonamide (1.39 g, 83% yield). MP: 169-170° C.

EXAMPLE 90 (−)44S)-344-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine

[0069] (−)-(4S)-3-(4-Chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine ([α²⁵ _(D)]=−165°, c=0.01, MeOH) was obtained as an amorphous solid via chiral chromatographic separation of racemic 3-(4-chlorophenyl)-N′-((4-chlorophenyl)sulfonyl)-N-methoxy-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboxamidine (Chiral stationary phase: Chiralpak AD). The mobile phase consisted of ethanol. 

1. Compounds of the general formula (I)

wherein R and R₁ independently represent phenyl, thienyl or pyridyl which groups may be substituted with 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group C₁₋₃-alkyl or alkoxy, hydroxy, halogen, trifluoromethyl, trifluoromethylthio, trifluoromethoxy, nitro, amino, mono- or dialkyl (C₁₋₂)-amino, mono- or dialkyl (C₁₋₂)-amido, (C₁₋₃)-alkyl sulfonyl, dimethylsulfamido, C₁₋₃-alkoxycarbonyl, carboxyl, trifluoromethylsulfonyl, cyano, carbamoyl, sulfamoyl and acetyl, or R and/or R₁ represent naphtyl, R₂ represents hydrogen, hydroxy, C₁₋₃-alkoxy, acetyloxy or propionyloxy, R₃ represents a hydrogen atom or a branched or unbranched C₁₋₈ alkyl group or a C₃₋₇ cycloalkyl group which alkyl group or cycloalkyl group may be substituted with a hydroxy group, R₄ represents a C₂₋₁₀ branched or unbranched heteroalkyl group, C₃₋₈ non-aromatic heterocycloalkyl group or C₄₋₁₀ non-aromatic heterocycloalkyl-alkyl group which groups contain one or more heteroatoms from the group (O, N, S) or a —SO₂— group, which C₂₋₁₀ branched or unbranched heteroalkyl group, C₃₋₈ non-aromatic heterocycloalkyl group or C₄₋₁₀ non-aromatic heterocycloalkyl-alkyl group may be substituted with a keto group, trifluoromethyl group, C₁₋₃ alkyl group, hydroxy, amino, monoalkylamino, or dialkylamino group or a fluoro atom, or R₄ represents an amino, hydroxy, phenoxy or benzyloxy group, or R₄ represents a C₁₋₈ alkoxy, C₃₋₈ alkenyl, C₅₋₈ cycloalkenyl or C₆₋₉ cycloalkenylalkyl group which groups may contain a sulphur, nitrogen or oxygen atom, a keto group or —SO₂— group, which alkoxy, alkenyl and cycloalkenyl groups may be substituted with a hydroxy group, a trifluoromethyl group, an amino group, a monoalkylamino group or dialkylamino group or a fluoro atom, or R₄ represents a C₂₋₅ alkyl group which alkyl group contains a fluoro atom, or R₄ represents an imidazolylalkyl group, benzyl, pyridylmethyl, phenethyl or thienyl group, or R₄ represents a substituted phenyl, benzyl, pyridyl, thienyl, pyridylmethyl or phenethyl group wherein the aromatic rings are substituted with 1, 2 or 3 of the substituents Y, wherein Y has the meaning as indicated above, or when R₃ is H or methyl, R₄ may represent a group NR₆R₇wherein R₆ and R₇ are the same or different and represent C₂₋₄ alkyl , C₂₋₄ trifluoroalkyl or R₆ represents a methyl group with the proviso that R₇ represents a C₂₋₄ alkyl group, or R₆ and R₇—together with the nitrogen atom to which they are bonded—form a saturated or unsaturated heterocyclic moiety having 4 to 8 ring atoms which heterocyclic moiety may contain an oxygen or sulphur atom or a keto group or —SO₂— group or an additional nitrogen atom, which saturated or unsaturated heterocyclic moiety may be substituted with a C₁₋₄ alkyl group, or R₃ and R₄ together with the nitrogen atom to which they are bonded form a saturated or unsaturated, monocyclic or bicyclic heterocyclic moiety having 4 to 10 ring atoms, which heterocyclic moiety may contain one or more atoms from the group (O, N, S) or a keto group or —SO₂— group, which moiety may be substituted with a C₁₋₄ alkyl, hydroxyalkyl, phenyl, thienyl, pyridyl, amino, monoalkylaminoalkyl, dialkylaminoalkyl, monoalkylamino, dialkylamino, aminoalkyl, azetidinyl, pyrrolidinyl, piperidinyl or hexahydro-1H-azepinyl group, R₅ represents benzyl, phenyl, thienyl or pyridyl which may be substituted with 1, 2, 3 or 4 substituents Y, wherein Y has the meaning as indicated above, which can be the same or different, or R₅ represents C₁₋₈ branched or unbranched alkyl, C₃₋₈ alkenyl, C₃₋₁₀ cycloalkyl, C₅₋₁₀ bicycloalkyl, C₆₋₁₀ tricycloalkyl or C₅₋₈ cycloalkenyl or R₅ represents naphtyl. and tautomers, prodrugs, stereoisomers and salts thereof.
 2. Pharmaceutical compositions containing a pharmacologically active amount of at least one compound as claimed in claim 1 as an active component.
 3. Method of preparing pharmaceutical compositions as claimed in claim 2 characterised in that a compound as claimed in claim 1 is brought in a form suitable for administration.
 4. Use of a compound as claimed in claim 1 for the preparation of a pharmaceutical composition for the treatment of disorders involving cannabinoid neurotransmission.
 5. Use as claimed in claim 4 characterised in that said disorders are psychiatric disorders such as psychosis, anxiety, depression, attention deficits, memory disorders, cognitive disorders, appetite disorders, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative disorders, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimers disease, epilepsy, Huntington's disease, Tourette's syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, stroke, spinal cord injury, neuroinflammatory disorders, plaque sclerosis, viral encephalitis, demyelinisation related disorders, as well as for the treatment of pain disorders, including neuropathic pain disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, gastric ulcers, diarrhoea and cardiovascular disorders. 